Drosophila Muscleblind Is Involved in troponin T Alternative Splicing and Apoptosis
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Other documents of the author: Miranda, M. Eugenia; Zhou, Lei; Artero, Ruben D.; García López, Amparo; Fernández Costa, Juan M.; Pascual, Maya; Vicente Crespo, Marta; Monferrer Sales, Lidón
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comunitat-uji-handle2:10234/8033
comunitat-uji-handle3:10234/8636
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Title
Drosophila Muscleblind Is Involved in troponin T Alternative Splicing and ApoptosisAuthor (s)
Date
2008Publisher
Public Library of Science (PLoS)ISSN
19326203Type
info:eu-repo/semantics/articleVersion
info:eu-repo/semantics/acceptedVersionSubject
Abstract
Background: Muscleblind-like proteins (MBNL) have been involved in a developmental switch in the use of defined cassette
exons. Such transition fails in the CTG repeat expansion disease myotonic dystrophy due, in ... [+]
Background: Muscleblind-like proteins (MBNL) have been involved in a developmental switch in the use of defined cassette
exons. Such transition fails in the CTG repeat expansion disease myotonic dystrophy due, in part, to sequestration of MBNL
proteins by CUG repeat RNA. Four protein isoforms (MblA-D) are coded by the unique Drosophila muscleblind gene.
Methodology/Principal Findings: We used evolutionary, genetic and cell culture approaches to study muscleblind (mbl)
function in flies. The evolutionary study showed that the MblC protein isoform was readily conserved from nematods to
Drosophila, which suggests that it performs the most ancestral muscleblind functions. Overexpression of MblC in the fly eye
precursors led to an externally rough eye morphology. This phenotype was used in a genetic screen to identify five
dominant suppressors and 13 dominant enhancers including Drosophila CUG-BP1 homolog aret, exon junction complex
components tsunagi and Aly, and pro-apoptotic genes Traf1 and reaper. We further investigated Muscleblind implication in
apoptosis and splicing regulation. We found missplicing of troponin T in muscleblind mutant pupae and confirmed
Muscleblind ability to regulate mouse fast skeletal muscle Troponin T (TnnT3) minigene splicing in human HEK cells. MblC
overexpression in the wing imaginal disc activated apoptosis in a spatially restricted manner. Bioinformatics analysis
identified a conserved FKRP motif, weakly resembling a sumoylation target site, in the MblC-specific sequence. Site-directed
mutagenesis of the motif revealed no change in activity of mutant MblC on TnnT3 minigene splicing or aberrant binding to
CUG repeat RNA, but altered the ability of the protein to form perinuclear aggregates and enhanced cell death-inducing
activity of MblC overexpression.
Conclusions/Significance: Taken together our genetic approach identify cellular processes influenced by Muscleblind
function, whereas in vivo and cell culture experiments define Drosophila troponin T as a new Muscleblind target, reveal a
potential involvement of MblC in programmed cell death and recognize the FKRP motif as a putative regulator of MblC
function and/or subcellular location in the cell [-]
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